Novel approaches to the use of hypomethylating agents in myeloid malignancies.

Impact of Hypomethylating Agent Therapy in Myelodysplastic Syndromes with Chromosome 3 Abnormalities

Clonal Dissection of MDS and Secondary AML Resolves Shared Splicing Neoantigens and Mechanistic Underpinnings of Hypomethylating Agent Therapeutic Response

Differences in the Mutational Landscape of Myeloid Malignancies (acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative neoplasm) and Their Clinical Impact

Immune Checkpoint Inhibitor Therapy for Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes: A Single-Center Experience

Encouraging Efficacy Observed in Bexmab Study: A Phase 1/2 Study to Assess Safety and Efficacy of Bexmarilimab in Combination with Standard of Care in Myeloid Malignancies

Clinical Characteristics of Patients with TP53 Multihit MDS and AML. a Single-Center Experience

A variety of epigenetic changes contribute to transcriptional dysregulation in myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). DNA methyltransferase (DNMT) inhibitors--azacitidine and decitabine--have significant activity in the treatment of MDS. Despite marked activity in myeloid malignancy, monotherapy with DNMT inhibitors is limited by low complete and partial response rates (7-20%) and median response durations of 15 months. As with classical cytotoxic therapy, the targeting of biologic pathways and mechanisms may best be accomplished using a combination of agents offering complementary mechanisms and synergistic pharmacodynamic interactions. The goal of this approach is to improve response rates, quality, and duration, and to minimize adverse events. There are a number of new therapies under development for the management of MDS and AML. This review article touches on some of the more promising combination regimens in various phases of investigation. The treatment of MDS and AML is undergoing rapid evolution. Cytogenetic complete remission and prolonged survival represent important goals. Incremental improvements in disease state and quality-of-life issues are also important for patients. Given the overall failure of cytotoxic chemotherapy in the achievement of cures in MDS and MDS-related AML, the application of less toxic, biologically directed agents may represent a more promising approach to treatment. Combination therapies with DNMT inhibitors using optimal dosing regimens to focus on methylation reversal with lower doses over longer periods of time, rather than direct cytotoxic effects, are beginning to suggest promising results in MDS and AML.

Outcome Of Patients With Myelodysplastic Syndrome (MDS) With Bone Marrow Blasts Between 10-30% Treated With Hypomethylating Agents Versus Intensive Chemotherapy

A Phase II Study of Azacitidine and Sirolimus for the Treatment of Acute Myeloid Leukemia (AML) Refractory to or Not Eligible for Intensive Chemotherapy or High Risk Myelodysplastic Syndrome (MDS)

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) originate from preleukemic hematopoietic conditions, such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS) and have variable outcomes despite the successful implementation of targeted therapies. The prognosis differs depending on the molecular subgroup. In patients with TP53 mutations, the most inferior outcomes across independent studies were observed. Myeloid malignancies with TP53 mutations have complex cytogenetics and extensive structural variants. These factors contribute to worse responses to induction therapy, demethylating agents, or venetoclax-based treatments. Survival of patients with biallelic TP53 gene mutations is often less than one year but this depends on the type of treatment applied. It is still controversial whether the allelic state of mutant TP53 impacts the outcomes in patients with AML and high-risk MDS. Further studies are needed to justify estimating TP53 LOH status for better risk assessment. Yet, TP53-mutated MDS, MDS/AML and AML are now classified separately in the International Consensus Classification (ICC). In the clinical setting, the wild-type p53 protein is reactivated pharmacologically by targeting p53/MDM2/MDM4 interactions and mutant p53 reactivation is achieved by refolding the DNA binding domain to wild-type-like conformation or via targeted degradation of the mutated protein. This review discusses our current understanding of p53 biology in MDS and AML and the promises and failures of wild-type and mutant p53 reactivation in the clinical trial setting.

Background: Management of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) are challenging in low-middle income countries (LMICs) due to lack of advanced diagnostics for risk stratification, restricted finances and lack of trained manpower and infrastructure for handling patients with intensive chemotherapy. Venetoclax when combined with hypomethylating agents (HMA) such as decitabine or azacitidine inhibit electron transport chain complex II resulting in metabolic disruption and eradication of leukemia stem cells (LSCs). Although widely used globally, limited data is available for its use and outcomes from LMICs. Objectives: In this study, we aim to evaluate the outcomes of AML and MDS patients treated with venetoclax and HMA combination therapy in a tertiary care center of Pakistan. Materials and Methods: We conducted a retrospective analysis on 96 patients of which 54 patients had AML and 42 had MDS. All patients received venetoclax combined with HMA at a single center from January 2020 to December 2024. The primary outcomes measured for AML were overall survival (OS), progression free survival (PFS) and response rates (complete remission [CR], partial remission [PR], stable disease [SD] and no response [NR]) while for MDS response was assessed as per International Working Group (IWG criteria). Secondary outcomes were treatment related toxicity (febrile neutropenia, deaths, tumor lysis syndrome) Results: A total of 96 patients were divided into AML cohort (n=54) and MDS cohort (n=42). AML cohort had a male-to-female ratio of 2:1 and a median age of 52 (IQR:37- 62.2). The overall survival (OS), disease free survival (DFS), overall response rate (ORR) and complete remission (CR) was 77.4%, 52.8%, 50% and 88.8% respectively. Of relapsed patients (n=9), only 1 patient responded to salvage therapy. The median OS and DFS for patients receiving salvage HMA was 75% and 12% respectively. Common treatment related toxicities included febrile neutropenia (FN) in 66.7% patients with no treatment related mortality. A total of 12.9% patients underwent consolidative HSCT and 18.5% received off label venetoclax maintenance. The MDS cohort (n=42) had a male-to- female ratio 9.5:1 with 51 years median age. The OS and DFS in MDS cohort were 59.5% and 44.4% respectively. Disease was relapsed in 21.1% patients and median time to response was 64 days. FN occurred in 54.8% patients. Karyotype analysis showed normal cytogenetics in 90.5%. A total of 17.1% MDS patients underwent consolidative HSCT and 12.2% received venetoclax maintenance. Conclusion: HMA-VEN combination therapy is a feasible and effective treatment for patients with MDS and AML presenting in a resource limited setting. However, the low CR rates and high incidence of febrile neutropenia compared to high-income countries underscores the need for better supportive care, comprehensive molecular testing and individualized treatment approaches.

Prior Therapy with DNA Methyltransferase Inhibitors (DNMTI) Predicts for Lower Remission Rates and Worse Survival In Secondary Acute Myeloid Leukemia Patients (sAML) Receiving Remission Induction Therapy

A Phase I/II Study of Combination of Azacitidine, Venetoclax and Pevonedistat in Patients with Newly-Diagnosed Secondary Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) with Hypomethylating Agent (HMA) Failure

Clinical Outcomes Following Frontline Chemotherapy for Patients with Myeloid Malignancies Harboring Splicing Factor Mutations

Pyrimethamine, a STAT3 Inhibitor, Synergizes with Venetoclax and Shows Efficacy in Hypomethylating Agent Resistant MDS and AML